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Gene expression profiling in human neurodegenerative disease

Abstract

Transcriptome study in neurodegenerative disease has advanced considerably in the past 5 years. Increasing scientific rigour and improved analytical tools have led to more-reproducible data. Many transcriptome analysis platforms assay the expression of the entire genome, enabling a complete biological context to be captured. Gene expression profiling (GEP) is, therefore, uniquely placed to discover pathways of disease pathogenesis, potential therapeutic targets, and biomarkers. This Review summarizes microarray human GEP studies in the common neurodegenerative diseases amyotrophic lateral sclerosis (ALS), Parkinson disease (PD) and Alzheimer disease (AD). Several interesting reports have compared pathological gene expression in different patient groups, disease stages and anatomical areas. In all three diseases, GEP has revealed dysregulation of genes related to neuroinflammation. In ALS and PD, gene expression related to RNA splicing and protein turnover is disrupted, and several studies in ALS support involvement of the cytoskeleton. GEP studies have implicated the ubiquitin–proteasome system in PD pathogenesis, and have provided evidence of mitochondrial dysfunction in PD and AD. Lastly, in AD, a possible role for dysregulation of intracellular signalling pathways, including calcium signalling, has been highlighted. This Review also provides a discussion of methodological considerations in microarray sample preparation and data analysis.

Key Points

  • Gene expression profiling (GEP) has advanced considerably over the past 5 years, and has provided important insight into mechanisms underlying neurodegenerative disease

  • In amyotrophic lateral sclerosis, GEP studies have consistently implicated certain biological structures and pathways, including the cytoskeleton, inflammation, protein turnover and RNA splicing

  • GEP studies in Parkinson disease have highlighted dysfunction of the ubiquitin–proteasome system, RNA splicing, mitochondrial function and inflammation

  • In Alzheimer disease, affected pathways identified by GEP analysis include neuroinflammation, mitochondrial function and calcium signalling

  • GEP studies have investigated selective vulnerability to neurodegeneration between patients and in different anatomical areas of the CNS, in order to characterize disease mechanisms, identify therapeutic targets and potentially inform development of individualized treatments

  • Technical aspects of GEP, including sample preparation, data analysis and validation, require careful consideration to optimize assays and yield reliable results

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Figure 1
Figure 2: Summary of the biological pathways that are consistently identified by gene expression profiling of human tissue samples from patients with amyotrophic lateral sclerosis, Alzheimer disease or Parkinson disease.

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Acknowledgements

The work of this group is supported by the Motor Neurone Disease Association, the Wellcome Trust, the Medical Research Council, and by a European Community 7th Framework Programme (FP7/2007-2013) under grant agreement number 259867 Euromotor to P. J. Shaw and J. Kirby; by a David Peake fellowship awarded to J. Cooper-Knock; and by BBSRC and EPSRC funding awarded to M. Rattray.

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J. Cooper-Knock researched the data for the article. J. Cooper-Knock, J. Kirby, P. R. Heath, M. Rattray and P. J. Shaw made substantial contributions to discussion of the article content. J. Cooper-Knock and L. Ferraiuolo wrote the article. J. Kirby, P. R. Heath, M. Rattray and P. J. Shaw contributed to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Pamela J. Shaw.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Summary of gene expression profiling studies conducted on human biosamples from patients with ALS (DOC 96 kb)

Supplementary Table 2

Summary of gene expression profiling studies conducted on human biosamples from patients with PD (DOC 110 kb)

Supplementary Table 3

Summary of gene expression profiling studies conducted on human biosamples from patients with AD (DOC 116 kb)

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Cooper-Knock, J., Kirby, J., Ferraiuolo, L. et al. Gene expression profiling in human neurodegenerative disease. Nat Rev Neurol 8, 518–530 (2012). https://doi.org/10.1038/nrneurol.2012.156

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